Physiologically Based Pharmacokinetic Modeling of Doravirine and Its Major Metabolite to Support Dose Adjustment With Rifabutin

Abstract

Doravirine, a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus 1 (HIV‐1), is predominantly cleared by cytochrome P450 (CYP) 3A4 and metabolized to an oxidative metabolite (M9). Coadministration with rifabutin, a moderate CYP3A4 inducer, decreased doravirine exposure. Based on nonparametric superposition modeling, a doravirine dose adjustment from 100 mg once daily to 100 mg twice daily during rifabutin coadministration was proposed. However, M9 exposure may also be impacted by induction, in addition to the dose adjustment. As M9 concentrations have not been quantified in previous clinical studies, a physiologically based pharmacokinetic model was developed to investigate the change in M9 exposure when doravirine is coadministered with CYP3A inducers. Simulations demonstrated that although CYP3A induction increases doravirine clearance by up to 4.4‐fold, M9 exposure is increased by only 1.2‐fold relative to exposures for doravirine 100 mg once daily in the absence of CYP3A induction. Thus, a 2.4‐fold increase in M9 exposure relative to the clinical dose of doravirine is anticipated when doravirine 100 mg twice daily is coadministered with rifabutin. In a subsequent clinical trial, doravirine and M9 exposures, when doravirine 100 mg twice daily was coadministered with rifabutin, were found to be consistent with model predictions using rifampin and efavirenz as representative inducers. These findings support the dose adjustment to doravirine 100 mg twice daily when coadministered with rifabutin.

Prediction of Maternal and Fetal Doravirine Exposure by Integrating Physiologically Based Pharmacokinetic Modeling and Human Placenta Perfusion Experiments

“…All simulations were performed using the Simcyp® PBPK Simulator, version 20 (Simcyp ® , Certara company, Sheffield, UK). Doravirine parameters described in an existing three-compartment PBPK model, which was validated in nonpregnant individuals and verified with drug–drug interaction studies, were used as starting points [ 5 , 6 ]. The model was optimized in terms of volume of distribution to allow use of the permeability-limited placenta model in Simcyp.…”

“…In short, the fetal (6 mL/min) and Doravirine is a first-line drug for patients living with HIV that is commonly prescribed in high-income countries because it has a favorable side effect profile, is not a perpetrator of drug-drug interactions, and has good efficacy [4]. Doravirine is a lipophilic compound (log P o:w 3.0) showing extensive tissue distribution and moderate plasma protein binding (76%) [5,6]. The major clearance route is mediated by hepatic cytochrome P450 (CYP)3A4, and renal clearance plays a minor role [6].…”

Current Practices, Gap Analysis, and Proposed Workflows for PBPK Modeling of Cytochrome P450 Induction: An Industry Perspective

“…This example demonstrates acceptance of PBPK modeling results for CYP3A induction by the FDA in lieu of clinical studies both as a victim and perpetrator and utility of an endogenous biomarker in prediction of CYP3A4-mediated DDI. Yee et al 25 present an example where PBPK modeling was used to predict levels of a circulating metabolite after CYP3A induction. Doravirine (PIFELTRO; Merck & Co., Inc., Kenilworth, NJ, USA) is a novel non-nucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus 1 (HIV-1).…”

“…doravirine is coadministered with rifabutin). 25 The FDA accepted the modeling results and the recommended dose adjustment and requested a postmarketing commitment study. In the subsequent clinical trial, doravirine and M9 exposures were found to be consistent with the model predictions.…”

“…Yee et al 25 . present an example where PBPK modeling was used to predict levels of a circulating metabolite after CYP3A induction.…”